Helicobacter pylori CagA elicits BRCAness to induce genome instability that may underlie bacterial gastric carcinogenesis
Helicobacter pylori CagA elicits BRCAness to induce genome instability that may underlie bacterial gastric carcinogenesis
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DOI：
10.1016/j.chom.2021.04.006
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发表时间：
2021-06-09
影响因子：
30.3
通讯作者：
Hatakeyama, Masanori
中科院分区：
文献类型：
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作者：
Imai, Satoshi;Ooki, Takuya;Hatakeyama, Masanori
感染CagA的幽门螺杆菌在胃癌的发展中起着致病作用。在递送到胃上皮细胞后，CagA去调节原癌磷酸酶SHP 2，同时通过复合物形成抑制极性调节激酶PAR 1b。在这里，我们发现CagA/PAR 1b相互作用通过抑制PAR 1b介导的BRCA 1磷酸化来破坏BRCA 1的核转位。因此，它诱导BRCAness，促进DNA双链断裂（DSB），同时使无错误同源重组介导的DNA修复失效。CagA/PAR 1b相互作用还刺激Hippo信号传导，从而避免DNA损伤细胞的凋亡，使细胞有时间通过易错机制修复DSBs。DSB激活的p53-p21（Cip 1）轴抑制CagA递送的细胞的增殖，但这种抑制可以通过p53失活来克服。事实上，TP 53突变细胞中CagA的连续脉冲驱动了具有BRCAnes相关遗传标记的体细胞突变。扩增CagA递送的具有BRCAness介导的基因组不稳定性的细胞，由此产生CagA非依赖性癌症易感细胞，提供了H. pylori CagA与胃癌发生的关系。
Infection with CagA-producing Helicobacter pylori plays a causative role in the development of gastric cancer. Upon delivery into gastric epithelial cells, CagA deregulates prooncogenic phosphatase SHP2 while inhibiting polarity-regulating kinase PAR1b through complex formation. Here, we show that CagA/PAR1b interaction subverts nuclear translocation of BRCA1 by inhibiting PAR1b-mediated BRCA1 phosphorylation. It hereby induces BRCAness that promotes DNA double-strand breaks (DSBs) while disabling error-free homologous recombination-mediated DNA repair. The CagA/PAR1b interaction also stimulates Hippo signaling that circumvents apoptosis of DNA-damaged cells, giving cells time to repair DSBs through error-prone mechanisms. The DSB-activated p53-p21(Cip1) axis inhibits proliferation of CagA-delivered cells, but the inhibition can be overcome by p53 inactivation. Indeed, sequential pulses of CagA in TP53-mutant cells drove somatic mutation with BRCAness-associated genetic signatures. Expansion of CagA-delivered cells with BRCAness-mediated genome instability, from which CagA-independent cancer-predisposing cells arise, provides a plausible "hit-and-run mechanism" of H. pylori CagA for gastric carcinogenesis.